A, Schematic figure of a fractal pattern of the Landolt ring. Several small lesions are connected to each other to form a large Landolt ring. Large lesions with a fractal pattern form a large letter C seen by retroillumination (B) and fluorescein staining (C) in patient 4. Large lesions with a fractal pattern on a slitlamp photograph with fluorescein staining in patient 6 form large circular lesions in the right (D) and left (E) eyes when small Landolt rings became connected.

ImportanceLandolt ring–shaped epithelial keratopathy is a newly identified disease with vesicular changes of unknown origin in the epithelial cells.

ObservationsEleven Japanese patients with specific epithelial lesions that resembled a Landolt ring in the corneal epithelium were assessed. The main symptoms of Landolt ring–shaped epithelial keratopathy are foreign-body sensation and photophobia. Slitlamp examination indicates that Landolt ring–shaped lesions located only in the corneal epithelium are randomly distributed and occur unilaterally, bilaterally, or asymmetrically. Small lesions are sometimes connected to each other to form a large Landolt ring in a fractal pattern. Confocal microscopy reveals that the Landolt ring lesions are vesicular changes in the epithelial cells from the basal cell layer to the superficial cell layer without inflammation. The lesions form for weeks to months with sporadic exacerbations and natural remissions with or without treatments. The outcomes do not include epithelial disorders in the affected corneas or visual disruptions.

Conclusions and RelevanceWe describe a new disease entity of unknown origin referred to as Landolt ring–shaped epithelial keratopathy, which is usually bilateral and characterized by specific Landolt ring–shaped focal epithelial lesions with vesicular changes only in the epithelial cells. The disorder has an insidious onset and self-limiting nature despite treatment and should be included in the differential diagnosis of corneal epithelial disorders.

Introduction

The Landolt ring, a characteristic standardized symbol used to measure visual acuity (VA) in the daily outpatient clinic, is a ring with a gap that resembles the letter C (Figure 1A).1 We describe 11 Japanese patients with specific epithelial lesions that resembled a Landolt ring in the corneal epithelium (Figure 1B). The institutional review board of Ehime University approved this study. All patients provided oral informed consent.

Report of Cases

Patient profiles are provided in eTable 1 in the Supplement. The patients were unrelated and not from the same hometown. The mean (SEM) patient age was 45.9 (5.3) years (age range, 17-73 years); 7 patients (64%) were in their 40s to early 50s. With bilateral disease (10 patients [91%]), the number of ring-shaped lesions differed between the eyes. The symptoms included a foreign-body sensation in 7 patients (64%), ocular pain in 5 patients (45%), or blurred vision in 4 patients (36%). Two patients (patients 2 and 3) had a history of dry eye, 2 (patients 5 and 9) had cataracts, 1 (patient 7) had allergic conjunctivitis, and 1 (patient 9) had glaucoma; 6 patients had no ocular complications before diagnosis. Regarding systemic disease, 2 patients (patients 4 and 5) had a history of cancer treatment, 1 (patient 1) had thyroid disease, and 1 (patient 6) had hepatitis and hypertension. No association was found with a systemic illness in any patients.

Clinical findings of the Landolt ring–shaped epithelial keratopathy are provided in eTable 2 in the Supplement. Eight patients initially had a VA of 20/20 or better; patients 5, 6, and 9 had VA in the worse affected eye below 20/20. The bilateral VA decrease in patients 5 and 9 resulted from cataracts. Only patient 6 had no ocular complications that led to decreased VA before disease onset. The intraocular pressure was not elevated in any patients. Slitlamp examination revealed the Landolt ring–shaped lesions in the corneal epithelium, which can be observed more easily with fluorescein staining (Figure 1). The Landolt ring–shaped lesions, which were randomly distributed on the cornea, were single or multiple in the diseased corneas and different sizes; the gap in the C shape was randomly located. The Landolt ring–shaped lesions appeared and disappeared over time with or without treatment. The lesions were unilateral, bilateral, or asymmetric. Although, in some cases, the Landolt lesions were independent of each other, several small lesions were connected to form a large Landolt ring (Figure 2A) in a fractal pattern, with a statistical similarity in form over a range of magnifications of many natural shapes, objects, and phenomena.2- 4Figure 2 shows representative fractal lesions of Landolt ring–shaped epithelial keratopathy in patients 4 and 6.

The keratopathy was restricted to the epithelium in all patients, with no corneal infiltration, edema, or endothelial changes. No anterior chamber inflammation or keratic precipitates were observed. No conjunctivitis was observed except in patient 7. The corneal sensitivity was measured using Cochet-Bonnet esthesiometry in patients 1, 2, 3, 4, 7, and 11; no decreased corneal sensitivities (60 mm) were observed. No funduscopy findings were apparent in any patients. Polymerase chain reaction was performed to detect human herpesvirus 1 to 8 DNA5- 7 on scraped corneal specimens and/or in tear samples from 6 patients (patients 1, 2, 3, 5, 7, and 11), of which results were negative for all patients.

The clinical course of the Landolt ring–shaped epithelial keratopathy is provided in eTable 3 in the Supplement. The Landolt ring–shaped lesions developed at clinical diagnosis in December in 5 patients (45%), March in 4 patients (36%), November in 1 patient (9%), and February in 1 patient (9%). The disease onset and resolution were within the first year after diagnosis. The periods of recurrence after the second year or later after the initial diagnosis were January to March of year 2 after diagnosis in patient 2; December to April of year 2 in patient 5; and December of year 2, November to May of year 3, and October to March of year 4 in patient 3. The months at onset of all 11 patients were October to March, and the periods during which the Landolt lesions were observed were October to June. The Landolt ring lesions tended to form in winter, especially with seasonal change. After development, the lesions gradually resolved (mean [SEM] time to resolution, 3.0 [0.6] months). The numbers and sizes of the Landolt ring lesions often repeatedly decreased and increased, and the severities varied during the disease course.

The slitlamp findings revealed that after lesion development, no epithelial disorders occurred in the affected corneas of any patients (Figure 3). No patients reported a visual disturbance, foreign-body sensation, or eye pain at the final examination. Landolt ring–shaped lesions recurred in 3 patients (27%) during the follow-up period. The mean (SEM) follow-up period from detection of this epithelial keratopathy was 11.0 (5.3) months (range, 2 weeks to 54 months). Topical treatments included a corticosteroid agent for 5 patients (45%), an immunosuppressive agent for 1 patient (9%), an antiallergic agent for 3 patients (27%), an antimicrobial agent for 5 patients (45%), artificial tears for 2 patients (18%), and an antiherpetic agent for 1 patient (9%). Two patients (18%) were untreated.

To obtain more detailed lesion characterization at the cellular level, in vivo confocal microscopy using the Heidelberg Retinal Tomograph II Rostock Cornea Module (Heidelberg Engineering)8,9 was performed. Figure 3I-M shows representative images of the Landolt ring–shaped lesions in patient 1. Superficial epithelial layer scanning revealed cellular ballooning and hyporeflective cytoplasmic changes (Figure 3I). Wing cell level scanning revealed hyperreflective nuclear and cell membranes (Figure 3J). Basal cell layer level scanning revealed ridge formation into the Landolt ring (Figure 3K). The bottom level of the basal cells had abnormal hyperreflective precipitates (Figure 3L). At the Bowman layer, the subbasal nerve plexus had normal morphologic features (Figure 3M). The long nerve fibers ran parallel to the Bowman layer.10 These findings indicate that the Landolt ring–shaped lesions formed as a result of morphologic changes; vesicular cellular ballooning in the basal cells was continuous with the superficial cellular layer only within the epithelial layer. Fluorescein staining of the Landolt ring–shaped lesions did not reveal epithelial erosion but revealed disruption of the epithelial junction from swelling of the epithelial cellular surface caused by serial cellular ballooning from the basal cell layer. The corneal stromal layer was normal without activated keratinocytes with highly reflective cellular bodies; the endothelial layer was normal. No Langerhans cells were seen around the lesions.

Discussion

We propose a new disease entity called Landolt ring–shaped epithelial keratopathy. Our 11 patients had interesting disease characteristics. This disease of unknown origin was usually chronic, bilateral, and characterized by a specific focal epithelial lesion that resembled the letter C and was composed of vesicular changes in the epithelial cell layer without apparent inflammation. The lesions often continued to appear for weeks to months with sporadic exacerbation and natural remission. Landolt ring disease differed from other previously described corneal epithelial disorders.11- 15 Although the current study described 11 Japanese patients with Landolt ring–shaped epithelial keratopathy, it is unclear whether this is relevant only to a Japanese population or worldwide. To our knowledge, no other patients currently have this condition. If this report draws worldwide attention to this disease, more information about its distribution may later be revealed. Genetic studies may be useful to clarify the features. The origin of Landolt ring–shaped corneal epitheliopathy is unknown, and further investigation is needed.